OBJECTIVE:To assess whether halothane exposure could influence contraction-relaxation coupling of human skeletal muscle with malignant hyperthermia susceptibility. STUDY DESIGNED: Laboratory investigation. MATERIAL AND METHODS:Muscle biopsies from 14 patients, including six classified as susceptible to MH (MHS) and eight as classified as non-susceptible (MHN) according to criteria of the European MH group. Mechanical parameters of strips were obtained before and after 3 vol% halothane exposure. The contraction and relaxation parameters were measured under isotonic and isometric conditions: maximum shortening and lengthening velocities (respectively maxVc and maxVr); peak of the positive (+dP/dtmax) and negative (-dP/dtmax) twitch tension derivative; ratio R1 = maxVc/maxVr and ratio R2 = (+dP/dtmax) (-dp/dtmax). RESULTS:In MHN muscle, halothane markedly increased maxVc and maxVr, so that the ratio R1 was unchanged. Both +dP/dtmax and -dP/dtmax increased such that the ratio R2 did not vary. In MHS muscle, halothane induced a significant decrease in maxVr (p < 0.05) without changes in maxVc, so that the ratio R1 increased significantly. +dP/dtmax remained unchanged whereas -dP/dtmax decreased significantly; the ratio R2 increased (p < 0.05). CONCLUSION:Our results indicated that, in MHN muscle the contractility property is improved with halothane exposure. In MHS muscle, halothane caused an impairment of relaxation. The mechanical abnormalities observed in this study might be related to sarcoplasmic reticulum dysfunction in MH diseases.

Objective: To assess whether halothane exposure could influence contraction- relaxation coupling of human skeletal muscle with malignant hyperthermia susceptibility.Study designed. Laboratory investigation.Material and methods: Muscle biopsies from 14 patients, including six classified as susceptible to MH (MHS) and eight as classified as non-susceptible (MHN) according to criteria of the European MH group. Mechanical parameters of strips were obtained before and after 3vol% halothane exposure. The contraction and relaxation parameters were measured under isotonic and isometric conditions: maximum shortening and lengthening velocities (respectively maxVc and maxVr); peak of the positive (+ dP/dt(max)) and negative (-dP/dt(max)) twitch tension derivative; ratio R1 = maxVc/ maxVr and ratio R2= (+ dP/dt(max)) (-dP/dt(max)).Results: In MHN muscle, halothane markedly increased maxVc and maxVr, so that the ratio R1 was unchanged. Both + dP/dt(max) and -dP/dt(max) increased such that the ratio R2 did not vary. In MHS muscle, halothane induced a significant decrease in maxVr (p < 0.05) without changes in maxVc, so that the ratio R1 increased significantly. + dP/ dt(max) remained unchanged whereas -dP/dt(max) decreased significantly; the ratio R2 increased (p < 0.05).Conclusion: Our results indicated that, in MHN muscle the contractility property is improved with halothane exposure. In MHS muscle, halothane caused an impairment of relaxation. The mechanical abnormalities observed in this study might be related to sarcoplasmic reticulum dysfunction in MH diseases. (C) 2002 Editions scientifiques et medicales Elsevier SAS.

Br J Anaesth 2000; 85: 129–35 Neuroleptic malignant syndrome (NMS) is a relatively rare but potentially fatal complication of the use of neuroleptic drugs. It was first described by Delay and colleagues after the introduction of neuroleptics in 1960; they called it ‘akinetic hypertonic syndrome’.16Delay J Pichot P Lempiere T Blissalde B Peigne F Un neuroleptique majeur non phenothiazinique et non réserpinique, l’halopéridol, dans le traitement des psychoses.Ann Med Psychol. 1960; 18: 145-152Google Scholar Over the last decade, almost 1000 cases of NMS have been reported, but many features of this syndrome remain controversial. Indeed, a graded scale of specific signs and symptoms for the diagnosis of NMS and a spectrum of clinical severity are two issues that await resolution.1Adityanjee PA Singh S Singh G Ong S Spectrum concept of neuroleptic malignant syndrome.Br J Psychiatr. 1988; 153: 107-111Crossref PubMed Scopus (67) Google Scholar 22Guze BH Baxter CR Current concepts. Neuroleptic malignant syndrome.New Engl J Med. 1985; 313: 163-166Crossref PubMed Scopus (253) Google Scholar Many diagnostic criteria have been proposed, but no single set of criteria has been adopted for general use. Different presentations of this disorder could explain some of the contradictory findings associated with NMS; these include the following: (i) prospective studies have provided disparate estimates of the frequency of NMS, ranging from 0.07%20Gelenberg AJ Bellinghausen B Wojcik JD Falk WE Sachs GS Aprospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital.Am J Psychiatr. 1988; 145: 517-518Crossref PubMed Scopus (76) Google Scholar to 2.2%26Hermesh H Aizenberg D Lapidot M Munitz H Risk of malignant hyperthermia among patients with neuroleptic malignant syndrome and their families.Am J Psychiatr. 1988; 145: 1431-1434Crossref PubMed Scopus (32) Google Scholar among patients receiving neuroleptic agents; (ii) risk factors for NMS vary in different patient populations;29Keck PE Pope H Cohen BM McElroy SL Nierenberg AA Risk factors for neuroleptic malignant syndrome.Arch Gen Psychiatr. 1989; 46: 914-918Crossref PubMed Scopus (218) Google Scholar and (iii) the association between NMS and other potentially fatal syndromes, such as malignant hyperthermia, is unclear. Two major, though not necessarily competing, theories to explain NMS are a neuroleptic-induced alteration of central neuroregulatory mechanisms and an abnormal reaction of predisposed skeletal muscle. This latter hypothesis is based on similarities between NMS and malignant hyperthermia and suggests that neuroleptic medications induce abnormal calcium availability in muscle cells of susceptible individuals and trigger muscle rigidity, rhabdomyolysis and hyperthermia. Alternatively, in some circumstances, it is possible that neuroleptics could be directly toxic to normal skeletal muscle. Dopamine plays a role in central thermoregulation in mammals. A dopamine injection into the preoptic–anterior hypothalamus causes a reduction in core temperature.14Cox B Kerwin R Lee TE Dopamine receptors in the central thermoregulatory pathways of the rat.J Physiol (Lond.). 1978; 282: 471-483Crossref Scopus (110) Google Scholar Since neuroleptic drugs block dopamine receptor sites, the hyperthermia associated with NMS may result from a blockade of hypothalamic dopamine sites. This was suggested 20 yr ago by Henderson and Wooten, who reported a patient with Parkinson's disease and chronic psychosis who developed NMS when dopaminergic agonists were withdrawn but haloperidol was continued.24Henderson VW Wooten GF Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade?.Neurology. 1981; 31: 132-137Crossref PubMed Google Scholar NMS has also been observed in a patient with Huntington's chorea taking methyltyrosine, a cathecholamine synthesis inhibitor, and tetrabenazine, which depletes central nervous system catecholamines.10Burke RE Fahn S Mayeux R Neuroleptic malignant syndrome caused by dopamine depleting drugs in a patient with Huntington's chorea.Neurology (NY). 1981; 31: 1022-1026Crossref PubMed Google Scholar This suggests that NMS is caused by dopamine depletion or blockade, leading to abnormal central thermoregulation. The dopamine blockade theory is supported by the report of a case in which NMS developed when l-dopa/carbidopa and amantadine were abruptly discontinued in a patient with Parkinson's disease who had never taken neuroleptics.50Toru M Matsuda O Makaguchi K Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drug.J Nervous Mental Dis. 1981; 169: 324-327Crossref PubMed Scopus (187) Google Scholar Some dopamine-function-enhancing drugs, such as bromocriptine9Bond WS Detection and management of the neuroleptic malignant syndrome.Clin Pharmacol. 1984; 3: 302-307PubMed Google Scholar or amantadine,36McCarron MM Boettger ML Peck JI A case of neuroleptic malignant syndrome successfully treated with amantadine.J Clin Psychiatr. 1982; 43: 381-382PubMed Google Scholar have shown efficacy in treating NMS. The blockade of dopamine receptors in the hypothalamus is thought to lead to impaired heat dissipation. In addition, blockade of dopamine receptors in the corpus striatum is thought to cause muscular rigidity, generating heat. The excess heat production, in association with a decrease in heat dissipation, produces hyperthermia, which is one of the main signs of the syndrome. The peripheral anticholinergic effects of neuroleptics which reduce sweating probably do not play a major role in hyperthermia associated with NMS since most NMS patients (70%) are in a sweat. However, it is unlikely that blockade of dopamine receptors in the hypothalamus and corpus striatum could completely explain all the signs of NMS. Indeed, hypothalamic thermoregulation involves noradrenergic, serotoninergic, cholinergic and central dopaminergic pathways.7Blingh J Cottle WH Maskrey M Influence of ambient temperature on the thermoregulatory responses to 5 hydroxy tryptamine, noradrenalin and acetylcholine injected into the lateral cerebral ventricles of sheep, goats and rabbits.J Physiol. 1971; 212: 377-392Crossref PubMed Scopus (144) Google Scholar Many neuroleptics may have additional selective effects on peptides co-transmitting with dopamine in the striatum and other parts of the brain. A common pathophysiology of NMS and malignant hyperthermia has been suggested.15Delacour JL Daoudal P Chapoutot JL Rocq B Traitement du syndrome malin des neuroleptiques par le dantrolène.Nouv Presse Méd. 1981; 10: 3572-3573PubMed Google Scholar 17Denborough MA Collins SP Hopkinson KC Rhabdomyolysis and malignant hyperpyrexia.Br Med J. 1985; ii: 1878Google Scholar 49Tollefson G A case of neuroleptic malignant syndrome: in vitro muscle comparison with malignant hyperthermia.J Clin Psychopharmacol. 1982; 2: 266-270PubMed Google Scholar This hypothesis is based mainly on three points: (i) NMS and malignant hyperthermia have clinical features in common, including hyperthermia, rigidity, an elevated creatine kinase concentration and a mortality rate for both NMS and malignant hyperthermia of 10–30%; (ii) sodium dantrolene, a peripheral muscle relaxant, has been used successfully in both syndromes; (iii) abnormal results have been found in in vitro contractility tests in patients with NMS or malignant hyperthermia. These in vitro halothane–caffeine tests are at present the most reliable diagnostic measure for patients susceptible to malignant hyperthermia.47The European Malignant Hyperpyrexia Group A protocol for the investigation of malignant hyperpyrexia susceptibility.Br J Anaesth. 1984; 56: 1267-1269Crossref PubMed Scopus (480) Google Scholar They determine the sensitivity of muscle fibres to halothane or caffeine added to the bathing solution. Muscle fibres from patients susceptible to malignant hyperthermia contract in response to these drugs at a lower concentration than those from normal patients. Hence, in order to evaluate a possible association between NMS and malignant hyperthermia, several investigators have used such tests on skeletal muscle fibres removed from patients with documented NMS episodes. However, conflicting results have been reported regarding the prevalence of malignant hyperthermia susceptibility among NMS patients.2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar 5Araki M Takagi A Higuchi I Sugita H Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology.Neurology. 1988; 38: 297-301Crossref PubMed Google Scholar 13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar Three main series and some sporadic case reports have been published. Caroff and colleagues13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar found that five of seven NMS patients were susceptible to malignant hyperthermia on the basis of a 3% halothane response. Araki and colleagues5Araki M Takagi A Higuchi I Sugita H Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology.Neurology. 1988; 38: 297-301Crossref PubMed Google Scholar showed, using a caffeine skinned fibre technique, that there was abnormal contracture in six NMS patients similar to that seen in malignant hyperthermia. Our laboratory2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar 32Krivosic-Horber R Adnet P Guevart E Theunynck D Lestavel P Neuroleptic malignant syndrome and malignant hyperthermia.Br J Anaesth. 1987; 59: 1554-1556Crossref PubMed Scopus (20) Google Scholar found that 13 of 14 NMS patients were not susceptible to malignant hyperthermia and the other was equivocal. One possible explanation for these discrepancies is that patients diagnosed as having NMS may be a heterogeneous group with great variability in clinical presentation, response to treatment and, possibly, response to test drugs. Some of the variation in the in vitro results from different centres may be attributable to variations in laboratory procedures. The variety of tests used for diagnosing malignant hyperthermia diagnosis included using caffeine alone,5Araki M Takagi A Higuchi I Sugita H Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology.Neurology. 1988; 38: 297-301Crossref PubMed Google Scholar halothane and caffeine on separate muscle bundles,32Krivosic-Horber R Adnet P Guevart E Theunynck D Lestavel P Neuroleptic malignant syndrome and malignant hyperthermia.Br J Anaesth. 1987; 59: 1554-1556Crossref PubMed Scopus (20) Google Scholar halothane with cumulative concentrations of caffeine,49Tollefson G A case of neuroleptic malignant syndrome: in vitro muscle comparison with malignant hyperthermia.J Clin Psychopharmacol. 1982; 2: 266-270PubMed Google Scholar or caffeine on skinned muscle fibres.5Araki M Takagi A Higuchi I Sugita H Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology.Neurology. 1988; 38: 297-301Crossref PubMed Google Scholar The sensitivity of this latter method may be inadequate as the technique itself excludes any detection of a possible defect in the sarcolemma.4Adnet PJ Krivosic-Horber RM Adamantidis MM Reyford H Cordonnier C Haudecoeur G Effects of calcium-free solution, calcium antagonists, and the calcium agonist BAY K 8644 on mechanical responses of skeletal muscle from patients susceptible to malignant hyperthermia.Anesthesiology. 1991; 75: 413-419Crossref PubMed Scopus (19) Google Scholar Differences were also observed in the criteria used for diagnosing malignant hyperthermia based on in vitro contracture tests:13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar some centres used the development of a contracture of >0.5 g force in response to 1% halothane as a threshold while others chose >0.7 g force in response to 3% halothane. The European malignant hyperthermia group17Denborough MA Collins SP Hopkinson KC Rhabdomyolysis and malignant hyperpyrexia.Br Med J. 1985; ii: 1878Google Scholar required, for an abnormal response to halothane, a contracture of ≥0.2 g force in response to <2% halothane. In other sporadic case reports, the protocol and diagnostic criteria were not fully explained. The time interval between adverse reaction to the neuroleptic drug and the biopsy was either not specified,5Araki M Takagi A Higuchi I Sugita H Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology.Neurology. 1988; 38: 297-301Crossref PubMed Google Scholar or was 1 month13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar or 2–3 weeks.2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar 32Krivosic-Horber R Adnet P Guevart E Theunynck D Lestavel P Neuroleptic malignant syndrome and malignant hyperthermia.Br J Anaesth. 1987; 59: 1554-1556Crossref PubMed Scopus (20) Google Scholar Caroff and colleagues13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar found no correlation between the maximum halothane response and the time between normalization of creatine kinase concentration and biopsy. However, contracture test results in NMS patients may be falsely positive and reflect coincidental changes in muscle resulting from NMS. For example, Gallant and colleagues19Gallant EM Fletcher TF Goettl VM Rempel WE Porcine malignant hyperthermia: cell injury enhances halothane sensitivity of biopsies.Muscle Nerve. 1986; 9: 174-184Crossref PubMed Scopus (29) Google Scholar reported that muscle fibre injury during biopsy and in vitro testing procedures enhances halothane sensitivity and could contribute to false-positive contracture test results. Denborough, Collins and Hopkinson17Denborough MA Collins SP Hopkinson KC Rhabdomyolysis and malignant hyperpyrexia.Br Med J. 1985; ii: 1878Google Scholar reported positive results in two patients who recovered from non-drug-related episodes of rhabdomyolysis. Adnet and colleagues3Adnet PJ Krivosic-Horber RM Adamantidis MM Haudecoeur G Reyford HG Dupuis BA Is resting membrane potential a possible indicator of viability of muscle bundles used in the in vitro caffeine contracture test?.Anesth Analg. 1991; 74: 105-111Crossref Scopus (41) Google Scholar found that if cut fibre specimens depolarize with time after biopsy, these preparations become less sensitive to caffeine, and so one must be cautious when interpreting the results of in vitro caffeine contracture test. This suggests that non-specific muscle damage secondary to metabolic factors, drug exposure, abnormalities in central nervous system activity or testing procedures may have contributed to the abnormal responses observed in vitro in muscle obtained from survivors of NMS episodes. Since our previous reports, 19 additional patients have been investigated according to the European malignant hyperthermia protocol. None of these patients were susceptible to malignant hyperthermia and two patients were equivocal. Statistical analysis for inferences based upon negative results can be performed. The increase in our study group size from 14 to 33 patients decreases the likelihood of malignant hyperthermia occurring in NMS patients from 31% to <10% with 95% confidence. Our study does not justify abandoning precautions against malignant hyperthermia in NMS patients. Mathematical analysis suggests that 59 consecutive NMS patients would have to test negative, with a similar in vitro protocol, in order to exclude statistically any cross-reactivity between malignant hyperthermia and NMS. Until such results are available, we suggest that all patients with clinical NMS should be tested for susceptibility to malignant hyperthermia before being considered at risk of this disorder during anaesthesia. Muscle contracture has been induced in vitro by neuroleptic agents such as chlorpromazine.31Kelkar VV Jindal MN Chlorpromazine-induced contracture of frog rectus abdominis muscle.Pharmacology. 1974; 12: 32-38Crossref PubMed Scopus (11) Google Scholar The drug is reported to influence calcium ion transport across the sarcoplasmic reticulum, and has been studied in various experimental muscle preparations. In a study on skinned fibres, chlorpromazine influenced both the contractile system and the function of the sarcoplasmic reticulum.45Takagi A Chlorpromazine and skeletal muscle: a study of skinned single fibers of the guinea pig.Exp Neurol. 1981; 734: 477-486Crossref Scopus (14) Google Scholar However, it has been shown previously that the drug induced contracture to the same extent in both NMS and normal muscle.2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar Likewise, Caroff and colleagues13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar also found no significant differences in the muscle response to another neuroleptic drug, fluphenazine, between NMS, malignant hyperthermia-susceptible and control patients. To explore further a possible direct action of neuroleptic drugs on skeletal muscle, we analysed the in vitro muscle contracture response to four neuroleptic agents implicated in NMS episodes.40Reyford HG Cordonner C Adnet PJ Krivosic-Horber RM Bonte CA The in vitro exposure of muscle strips from patients with neuroleptic malignant syndrome cannot be correlated with the clinical features.J Neurol Sci. 1990; 98: 527Google Scholar Muscle from NMS patients was no more sensitive to neuroleptic drugs than muscle from normal patients. These negative findings may indicate that the in vitro contracture response to neuroleptic agents does not correlate with clinical evidence of NMS. However, this may also show that neuroleptics are potentially active on skeletal muscle. Thus, it is possible that, in some circumstances, such as exhaustion, psychomotor agitation or dehydration, which are not explored by the in vitro method, neuroleptics may be toxic to skeletal muscle, leading to contracture and rhabdomyolysis. Therefore, neuroleptic contracture tests may not adequately reproduce conditions in vivo. Many factors present in vivo, such as neuroleptic metabolites, central dopaminergic blockade and risk factors for NMS, should be taken into consideration in developing more precise pharmacological models to explore possible interactions between neuroleptics and skeletal muscle function. Of particular interest is the fact that rechallenge with the original agent may not result in a recurrence of NMS. This suggests that neuroleptics may be a necessary, but not exclusive, cause of the syndrome.12Caroff SN The neuroleptic malignant syndrome.J Clin Psychiatr. 1980; 41: 79-83PubMed Google Scholar 34Levenson JL Neuroleptic malignant syndrome.Am J Psychiatr. 1985; 142: 1137-1145Crossref PubMed Scopus (607) Google Scholar Very recently, an experimental model for NMS has been developed. Rabbits treated with haloperidol and exposed to high ambient temperature may be useful in elucidating the pathogenesis of NMS.46Tanii H Taniguchi N Niigawa H et al.Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia and high serum creatine phosphokinase level.Brain Res. 1996; 743: 263-270Crossref PubMed Scopus (18) Google Scholar The molecular basis for NMS is unclear, but studies suggest that genetic factors are involved in its pathogenesis.27Kawanishi C Hanihara T Maruyama Y et al.Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.Psychiatr Gen. 1997; 7: 127-129Crossref PubMed Scopus (12) Google Scholar Involvement of the serotonergic system in NMS has been suggested, but polymorphisms in the 5-HT1A and 5-HT2A receptor genes do not determine susceptibility to NMS.28Kawanishi C Hanihara T Shimoda Y et al.Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5HT2A receptor genes.Am J Psychiatr. 1998; 155: 1275-1277Crossref PubMed Scopus (25) Google Scholar Other studies do not support an association between NMS and the mutations in the ryanodine receptor gene reported with malignant hyperthermia.38Miyatake R Iwahashi K Matsushita M Nakamura K Suwaki H No association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated with malignant hyperthermia.J Neurol Sci. 1996; 143: 161-165Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar NMS typically develops over a period of 24–72 h but many investigators have described a more insidious evolution of symptoms. The risk of developing NMS has been reported to last for 10–20 days after oral neuroleptics are discontinued and even longer when associated with depot forms of the drugs. Consistent diagnostic criteria have been used only in some clinical studies.29Keck PE Pope H Cohen BM McElroy SL Nierenberg AA Risk factors for neuroleptic malignant syndrome.Arch Gen Psychiatr. 1989; 46: 914-918Crossref PubMed Scopus (218) Google Scholar, 30Keck PE Harrisson G Pope JR McElroy SL Declining frequency of neuroleptic malignant syndrome in a hospital population.Am J Psychiatry. 1991; 148: 880-882Crossref PubMed Scopus (74) Google Scholar, 31Kelkar VV Jindal MN Chlorpromazine-induced contracture of frog rectus abdominis muscle.Pharmacology. 1974; 12: 32-38Crossref PubMed Scopus (11) Google Scholar Three major symptoms indicate a high probability of the presence of NMS: hyperthermia, rigidity and an elevated creatine phosphokinase concentration, reflecting rhabdomyolysis34Levenson JL Neuroleptic malignant syndrome.Am J Psychiatr. 1985; 142: 1137-1145Crossref PubMed Scopus (607) Google Scholar (Table 1). In the absence of these criteria, the diagnosis of NMS should be questioned, since other symptoms of the disorder may be seen in patients taking neuroleptics without having NMS. Elevated temperature (≥38.5°C) in the absence of other systemic illness is observed in most patients. Muscle rigidity consists of a generalized ‘lead pipe’ increase in tone which may result in decreased chest-wall compliance with resulting tachypnoeic hypoventilation and pulmonary infection secondarily. This increase in muscle tone may be accompanied by extrapyramidal symptoms including dyskinesia, dysarthria or Parkinsonism. The creatine phosphokinase concentration is always elevated (>1000 IU litre−1), reflecting myonecrosis secondary to intense muscle contracture. This often results in acute myoglobinuric renal failure. Minor signs alone do not indicate a high probability of NMS. Diaphoresis, tachycardia and abnormally high arterial pressure are common signs of autonomic dysfunction. Altered consciousness ranges from agitation to stupor or coma. Many other clinical signs of lesser frequency have been reported, including opisthotonos, grand mal seizures, Babinski's signs, chorea and trismus.Table 1Criteria for guidance in the diagnosis of neuroleptic malignant syndrome. The presence of all three major, or two major and four minor, manifestations indicates a high probability of the presence of neuroleptic malignant syndrome, if supported by clinical history (e.g. not indicative of malignant hyperthermia) (from reference 34Levenson JL Neuroleptic malignant syndrome.Am J Psychiatr. 1985; 142: 1137-1145Crossref PubMed Scopus (607) Google Scholar)CategoryManifestationsMajorFever, rigidity, elevated creatine phosphokinase concentrationMinorTachycardia, abnormal arterial pressure, tachypnoea, altered consciousness, diaphoresis, leucocytosis Open table in a new tab Leucocytosis, ranging from a slight elevation to 30 000 mm−3, is the only frequent laboratory finding included in the minor signs of NMS. Other non-specific laboratory abnormalities have been reported, such as mildly elevated hepatic enzymes (transaminase, lactic dehydrogenase and alkaline phosphatase). Non-specific encephalopathy may occur. Lumbar puncture should be done for the differential diagnosis but is usually normal in NMS. Cerebral CT scan is normal; non-specific changes are usually observed in muscle biopsy or post-mortem histopathological studies of the brain. Some authors are in favour of an approach whereby a diagnosis of NMS is only made if certain signs are present. For example, Levenson34Levenson JL Neuroleptic malignant syndrome.Am J Psychiatr. 1985; 142: 1137-1145Crossref PubMed Scopus (607) Google Scholar suggests that the presence of all three major, or two major and four minor signs (Table 1) indicates a high probability of NMS. These criteria for guidance in the diagnosis of NMS are commonly used in clinical research studies.2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar 13Caroff SN Rosenberg H Fletcher JE Heiman-Patterson TD Mann SC Malignant hyperthermia susceptibility in neuroleptic malignant syndrome.Anesthesiology. 1987; 67: 20-25Crossref PubMed Scopus (66) Google Scholar Similarly, Pope, Keck and McElroy39Pope AG Keck PE McElroy SL Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital.Am J Psychiatr. 1986; 143: 1227-1233Crossref PubMed Google Scholar have published ‘definite’ and ‘probable’ criteria for NMS. Others still prefer to think in terms of a spectrum of neuroleptic-related neurotoxicity, with varying combinations that enhance the potential for inappropriate diagnosis or management.35Levinson DF Simpson GM The treatment and management of neuroleptic malignant syndrome.Prog Neuropsychopharmacol Biol Psychiatr. 1992; 16: 425-443Crossref PubMed Scopus (18) Google Scholar A decrease in mortality from NMS has been reported in recent years. NMS resulted in a 76% mortality before 1970, a 22% mortality from 1970 to 1980, and a 15% mortality since 1980. Shalev, Hermesh and Munitz44Shalev A Hermesh H Munitz H Mortality from neuroleptic malignant syndrome.J Clin Psychiatr. 1989; 50: 18-25PubMed Google Scholar reported a significant decrease in mortality since 1984 (to 11%), which occurred independently of the treatment used: dopamine agonist or dantrolene. Renal failure is a strong predictor of mortality, representing a mortality risk of approximately 50%. A wide variety of antipsychotic agents is associated with this syndrome, including phenothiazines, butyrophenones, thioxanthenes, benzamides and miscellaneous novel antipsychotic agents such as clozapine and risperidone.23Hasan S Buckley P Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique.Am J Psychiatr. 1998; 155: 1113-1116Crossref PubMed Scopus (149) Google Scholar Other circumstances, such as abrupt discontinuation of neuroleptic or antiparkinsonian agents, and the use of dopamine-depleting agents, have also been reported to produce NMS. The onset of the syndrome is not related to the duration of exposure to neuroleptics or to toxic overdose. All ages (including children) and both genders are affected in NMS but young adult males predominate among reported cases. Cases have been reported in both psychiatric and medical patients including after multiple trauma or preoperative use of neuroleptic agents. Alcoholic patients are at greater risk of developing NMS during treatment of delirium or its prevention by droperidol or tiapride.2Adnet PJ Krivosic-Horber RM Adamantidis MM et al.The association between the neuroleptic malignant syndrome and malignant hyperthermia.Acta Anaesthesiol Scand. 1989; 33: 676-680Crossref PubMed Scopus (41) Google Scholar Abnormalities of muscle metabolism in alcoholic patients are caused by ethanol toxicity and malnutrition.8Bollaert PE Robin-Lherbier B Escange JM et al.Phosphorus nuclear magnetic resonance: evidence of abnormal skeletal muscle metabolism in chronic alcoholics.Neurology. 1989; 39: 821-824Crossref PubMed Google Scholar This may sensitize the muscle to the action of neuroleptics. In a psychiatric population, several studies6Berardi D Amore M Keck PE Troia M Dellatti M Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study.Biol Psychiatr. 1998; 44: 748-754Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar 30Keck PE Harrisson G Pope JR McElroy SL Declining frequency of neuroleptic malignant syndrome in a hospital population.Am J Psychiatry. 1991; 148: 880-882Crossref PubMed S

To assess the reactivity of sarcoplasmic reticulum to caffeine, using the skinned muscle fibre tension test and to compare it with the reference in vitro contracture test in the diagnosis of malignant hyperthermia (HM) susceptibility.Laboratory investigation.Muscle biopsies from 63 patients, including 29 classified as susceptible to MH (MHS) and 34 classified as non-susceptible (MHN) according to criteria of the European and the North American MH groups.The reactivity to caffeine and halothane of skinned muscle fibres was compared, according to the type of fibres, with the data of the in vitro contracture test. The type of fibres (type I: oxidative, slow; type II: glycolytic, fast) were determined with strontium dose-response curves.The reactivity to caffeine was significantly lower in the MHS group, for both type I and type II skinned fibres. However, in comparison with the data of the in vitro contracture tests, using the ROC curve analysis, the best sensitivity-specificity compromise was 90%-71% and 74%-84% for type I and type II skinned fibres respectively.The skinned muscle fibre tension test cannot be used instead of the in vitro contracture test for the diagnostic of MHS. However, it may strengthen the data of the latter.

Objective: To evaluate the practice of anaesthesia in French-speaking subsaharian countries.Type of study: Prospective surveyPersons: Two hundred seventeen nurse anaesthetists, from 11 different countries.Methods: Anonymous questionnaire.Results: One third of nurses were practising anaesthesia since less than five years and 1/3 since more than 10. Only 39 (18%) were working in the country side. Thirty seven (17%) had been trained outside subsaharian Africa tin Cuba 6%, France 5%, Morocco 5% and Germany 1% respectively). Two hundred thirteen (98%) were performing general anaesthesia and 169 (78%) regional anaesthesia. Hundred sixty eight (97%) used spinal anaesthesia, 57 (33%) epidural, 31 (18%) intravenous regional anaesthesia, 24 (14%) axillary block, 17 (10%) caudal block and 10 (6%) peripheral block respectively. For regional techniques, disposable devices were available in 50% of cases. For general anaesthesia, thiopental was administered by 193 (89%) and ketamine by 156 (72%) nurse anaesthetists respectively. In 50% of cases, these drugs were used alone. An ECG was available in 40%, a pulse oximeter in 14% and a capnographe in less than 2% of cases. A ventilator was present in 66% of the places, but used only in 30% of them because of the lack of maintenance and training.Conclusions: In this study, 50% of nurse anaesthetists were working alone. However, this rate is probably underestimated I as the questionnaire did not consider anaesthesia practice in the country side. (C) 1999 Elsevier, Paris.

- Thermoregulation -Hyperthermie maligne anesthesique ○ Physiopathologie ○ Diagnostic clinique de la crise ○ Diagnostic differentiel ○ HMA et autres myopathies ○ Diagnostic pharmacologique de la sensibilite a l'hyperthermie maligne ○ Traitement de l'HMA - Transfert en reanimation Quand transferer? Qui transferer? Evolution ○ Prise en charge d'un patient sensible a l'HMA - Coup de chaleur et hyperthermie maligne d'effort - Le syndrome malin des neuroleptiques - Hyperthermies malignes toxiques - Hyperthermies endocriniennes - Consequences d'une hyperthermie - Conclusion.

Chloroquine poisoning can cause life threatening cardiovascular disturbances. We report three cases of suicide with chloroquine causing acute respiratory insufficiency from pulmonamry oedema with lethal outcome, despite a treatment with diazepam, epinephrine and mechanical ventilation. (C) 1999 Elsevier, Paris.

OBJECTIVE:To evaluate the practice of anaesthesia in French-speaking subsaharian countries.TYPE OF STUDY:Prospective survey.PERSONS:Two hundred seventeen nurse anaesthetists, from 11 different countries.METHODS:Anonymous questionnaire.RESULTS:One third of nurses were practising anaesthesia since less than five years and 1/3 since more than 10. Only 39 (18%) were working in the country side. Thirty seven (17%) had been trained outside subsaharian Africa (in Cuba 6%, France 5%, Morocco 5% and Germany 1% respectively). Two hundred thirteen (98%) were performing general anaesthesia and 169 (78%) regional anaesthesia. Hundred sixty eight (97%) used spinal anaesthesia, 57 (33%) epidural, 31 (18%) intravenous regional anaesthesia, 24 (14%) axillary block, 17 (10%) caudal block and 10 (6%) peripheral block respectively. For regional techniques, disposable devices were available in 50% of cases. For general anaesthesia, thiopental was administered by 193 (89%) and ketamine by 156 (72%) nurse anaesthetists respectively. In 50% of cases, these drugs were used alone. An ECG was available in 40%, a pulse oximeter in 14% and a capnographe in less than 2% of cases. A ventilator was present in 66% of the places, but used only in 30% of them because of the lack of maintenance and training.CONCLUSIONS:In this study, 50% of nurse anaesthetists were working alone. However, this rate is probably under-estimated, as the questionnaire did not consider anaesthesia practice in the country side.

Objective: To assess the course of the demography of anaesthesia providers in French-speaking subsaharian countries. Type of study: Retrospective survey. Persons: Doctors trained in anaesthesia and nurse anaesthetists registered in West African medical societies. Methods: Countries, hospitals, anaesthesia manpower, seniority and place of training were analysed. Results: In the 13 French-speaking subsaharian countries including 97.5-M inhabitants, 122 doctors and 868 nurses were registered as anaesthetists in 1998. Mean ratios were one doctor trained in anaesthesia for 799,180 inhabitants and one nurse anaesthetist for 112,327 inhabitants. From 1980 to 1998, these figures increased by a factor 11 for doctors (+1100%) and by a factor two for nurses (+100%). Most doctors were working in the chief town, in both public and private health care institutions. Conclusions: In all French-speaking subsaharian countries, a major shortage of doctors trained in anaesthesia is existing. (C) 1999 Elsevier, Paris.

OBJECTIVE:To assess the course of the demography of anaesthesia providers in French-speaking subsaharian countries.TYPE OF STUDY:Retrospective survey.PERSONS:Doctors trained in anaesthesia and nurse anaesthetists registered in West African medical societies.METHODS:Countries, hospitals, anaesthesia manpower, seniority and place of training were analysed.RESULTS:In the 13 French-speaking subsaharian countries including 97.5-M inhabitants, 122 doctors and 868 nurses were registered as anaesthetists in 1998. Mean ratios were one doctor trained in anaesthesia for 799,180 inhabitants and one nurse anaesthetist for 112,327 inhabitants. From 1980 to 1998, these figures increased by a factor 11 for doctors (+1100%) and by a factor two for nurses (+100%). Most doctors were working in the chief town, in both public and private health care institutions.CONCLUSIONS:In all French-speaking subsaharian countries, a major shortage of doctors trained in anaesthesia is existing.

Objective: To assess the reactivity of sarcoplasmic reticulum to caffeine, using the skinned muscle fibre tension test and to compare it with the reference in vitro contracture test in the diagnosis of malignant hyperthermia (HM) susceptibility.Study designs Laboratory investigation.Materials Muscle biopsies from 63 patients, including 29 classified as susceptible to MH (MHS) and 34 classified as non-susceptible (MHN) according to criteria of the European and the North American MH groups.Methods The reactivity to caffeine and halothane of skinned muscle fibres was compared, according to the type of fibres, with the data of the in vitro contracture test. The type of fibres (type I: oxidative, slaw;type II: glycolytic, fast) were determined with strontium dose-response curves.Results: The reactivity to caffeine was significantly lower in the MHS group, for both type I and type II skinned fibres. However, in comparison with the data of the in vitro contracture tests, using the ROC curve analysis, the best sensitivity-specificity compromise was 90%-71% and 74%-84% for type I and type II skinned fibres respectively.Conclusion: The skinned muscle fibre tension test cannot be used instead of the in vitro contracture test for the diagnostic of MHS. However, it may strengthen the data of the latter. (C) 1999 Elsevier, Paris.

Chloroquine poisoning can cause life threatening cardiovascular disturbances. We report three cases of suicide with chloroquine causing acute respiratory insufficiency from pulmonary oedema with lethal outcome, despite a treatment with diazepam, epinephrine and mechanical ventilation.

Objectif : Évaluer, en milieu tropical africain, le risque lié à la pratique de la rachianesthésie (RA).Type d'étude : Enquête prospective multicentrique sur deux ans.Investigateurs : Vingt et un médecins anesthésistes-réanimateurs et infirmiers anesthésistes exerçant dans dix pays africains.Méthodes : Deux questionnaires anonymes : l'un, rempli à l'occasion de chaque complication, avait pour but de définir le type de l'incident ou de l'accident, d'en préciser les circonstances ; l'autre devait permettre de définir le poste occupé, de quantifier l'activité anesthésique globale et le nombre des RA pratiquées par rapport aux autres techniques et d'évaluer le nombre des complications et des décès en rapport avec une RA.Résultats : Six médecins anesthésistes-réanimateurs et une infirmière anesthésiste ont répondu à l'enquête. Six sites répartis sur cinq pays différents (Sénégal, Tchad, République centrafricaine, Niger, Madagascar) ont participé et ont réalisé 18 432 actes d'anesthésie dont 2 703 RA, ce qui représente 14,7 % de l'activité anesthésique. L'anesthésie générale prédominait avec une fréquence supérieure à 75 % dans les centres bien équipés. En revanche, dans les centres peu équipés ou dont l'approvisionnement était plus aléatoire la rachianesthésie a été la technique la plus utilisée avec une fréquence qui variait de 48,9 à 68,7 %. Quarante incidents et accidents (1,5 %) ont été rapportés dont cinq (0,2 %) ont entraîné le décès du patient. Sur les sept arrêts cardiocirculatoires (0,3 %), quatre ont été fatals (0,1 %). Huit des dix accidents et tous les décès ont eu lieu dans les sites peu équipés. Huit des dix accidents ont eu lieu au cours de césariennes réalisées en urgence. Tous les arrêts cardiocirculatoires étaient secondaires à une hypovolémie majeure d'installation brutale. Pour les quatre décès après arrêt cardiocirculatoire, la RA a été réalisée par un infirmier anesthésiste et avec de la bupivacaïne isobare 0,5 %.Conclusions : La pratique de la RA en milieu tropical africain était caractérisée par des conditions d'exercice et une qualification des personnels différentes par rapport à la France. La fréquence des arrêts cardiocirculatoires y était cinq fois plus importante et celle des décès 20 fois plus. Il est discutable d'avoir recours à la RA pour césarienne de sauvetage en situation d'hypovolémie. Une formation spécifique des infirmiers anesthésistes à la pratique des anesthésies locorégionales et d'une formation à la démarche qui conduit au choix d'une technique d'anesthésie adaptée à la chirurgie, à l'état du patient et aux moyens disponibles est à considérer en Afrique.Objective: To evaluate the risk of the practice of spinal anaesthesia (SA) in African tropics.Study design: Prospective study in multiple centres over a two years period.Persons: Twenty-one anaesthesiologists and anaesthetist nurses covering ten African countries.Methods: Two anonymous questionnaires; the first, filled in each anaesthetic problem occurred, to define the type of incident or accident, and its circumstances; the second was designed to define the position occupied, to quantify the global anaesthetic activity, the number of SA, and to value the number of complications or deaths linked to SA.Results: Six anaesthesiologists and one anaesthetist nurse replied to the study, covering six sites in five different countries (Senegal, Chad, Central African Republic, Niger and Madagascar). On the 18,432 anaesthetic acts collected, 2,703 (14.7%) were SA. In the well-equipped centres, general anaesthesia was predominant with a frequency of over 75%. However in the not so well equipped centres or those which supplies were more problematical, SA technique was used with a frequency varying from 48.9 to 68.7%. Forty incidents and accidents were reported (1.5%), five led to the death of the patient (0.2%). Among the seven cardiac arrests (0.3%), four were fatal (0.1%). Eight of the ten accidents and all of the deaths occurred in the least equipped centres. Eight of ten accidents happened during emergency caesarean sections. All cardiac arrests were preceded by a severe hypovolemia. For the four deaths after cardiac arrest, an anaesthetist nurse with isobaric bupivacaine 0.5% carried out SA.Conclusions: This study showed that the practice of SA in African tropics was performing in different practice conditions and people qualification than they were in France. The frequency of cardiac arrests and deaths was respectively five and 20 times more important, in those conditions. The first conclusion that can be drawn from this study is that it is questionable to use SA for emergency Caesarean section under hypovolemic condition. The second is the necessity for specific training on the local anaesthesia for anaesthetist nurses but also training to choose the anaesthesia best adapted to the surgery, the condition of the patient and the means available.

Objective: The aim was to determine whether myofilament Ca2+ sensitivity is altered in skinned cardiac fibres from endotoxin-treated rabbits. Methods: Endotoxin was injected i.v.. in conscious New-Zealand White rabbits at a dose of 0,5 mg/kg (groups I, II, and III) or 1 mg/kg (group IV). A fifth group was used as control. Hearts were excised 4 h (groups I and IV), 24 h (group II), or 5 days (C-roup III) after injection. Skinned fibres were obtained with chemical (EGTA + Brij 58) treatment of bundles isolated from papillary muscles. Results: The maximal Ca2+-activated force (F-o) of skinned cardiac fibres was not different between groups. However, [Ca2+] required to evoke 50% of F-o (Ca-50) was higher in the fibres from group I than in controls (1.78 +/- 0.05 vs. 1,53 +/- 0.03 mu M; P < 0.05). This effect was dose-dependent (group IV: Ca-50 = 2.08 +/- 0.12 mu M; P < 0.05 vs. group I), larger after 24 h (group II: Ca-50 = 2.12 +/- 0.05 mu M; P < 0.05 vs, group I). By 5 days, myofilament Ca2+ sensitivity had returned to normal (group III: Ca,, = 1.53 +/- 0.05 mu M). Conclusion: Myofilament Ca2+ sensitivity is decreased in skinned fibres taken from rabbit myocardium after i.v. endotoxin injection. This effect is dose- and time-dependent, and reversible with time. (C) 1998 Elsevier Science B.V. All rights reserved.

To compare three techniques of brachial plexus blockade for emergency surgery of the upper limb.Prospective, randomised study.One hundred eleven patients admitted to an emergency surgical service, randomly assigned to three groups.The patients were given 2% lidocaine with epinephrine 20 mL and 0.5% bupivacaine 20 mL. The three groups were as follows: brachial plexus block using a peripheral nerve stimulator (group St, n = 38); transarterial brachial plexus blockade with injection of 2/3 of the anaesthetic in back of and 1/3 in front of the artery (group TAP, n = 36); transarterial brachial plexus blockade with one single injection in back of the artery (group TP, n = 37). The success rate, time required to perform the technique, latency of analgesia, quality of motor blockade, and adverse effects were compared between the three groups. Analysis of variance was used to compare quantitative data and chi 2 test were used for qualitative data.Rates of success varied between 65 and 75%. Success rates, latency of analgesia and quality of motor blockade were not significantly different between groups. Time to perform the technique was longer when using a nerve stimulator.As these three techniques for brachial plexus block in emergency surgery are comparable, no one can be recommended instead of the others.

Objectives: To compare three techniques of brachial plexus blockade for emergency surgery of the upper limb.Study design: Prospective, randomised study.Patients: One hundred eleven patients admitted to an emergency surgical service, randomly assigned to three groups.Methods: The patients were given 2% lidocaine with epinephrine 20 mt and 0.5% bupivacaine 20 mt, The three groups were as follows: brachial plexus block using a peripheral nerve stimulator (group St, n = 38); transarterial brachial plexus blockade with injection of 2/3 of the anaesthetic in back of and 1/3 in front of the artery (group TAP, n = 36); transarterial brachial plexus blockade with one single injection in back of the artery (group TP, n = 37), The success rate, time required to perform the technique, latency of analgesia, quality of motor blockade, and adverse effects were compared between the three groups. Analysis of variance was used to compare quantitative data and chi(2) test were used for qualitative data.Results: Rates of success varied between 65 and 75%. Success rates, latency of analgesia and quality of motor blockade were not significantly different between groups. Time to perform the technique was longer when using a nerve stimulator.Conclusion: As these three techniques for brachial plexus block in emergency surgery are comparable, no one can be recommended instead of the others. (C) 1998 Elsevier, Paris.